Project Summary Infectious disease is the third-leading cause of death in the United States, and hospital-acquired infections (HAIs) in particular affect 1.7 million patients annually. The most common type of HAI is pneumonia, often caused by multi-drug resistant (MDR) pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii. Rates of antibiotic resistance for these bacteria in hospital- and ventilator-acquired pneumonia (HAP and VAP, respectively) have escalated significantly, in some cases exceeding 45%. There is a clear and urgent unmet medical need for new therapeutic strategies to treat HAP and VAP that can improve patient outcomes and combat the rising rates of antibiotic resistance associated with HAIs. As a novel approach to address this expanding medical need, Arrevus is pioneering the development of Designer Proline-rich antimicrobial peptide Chaperone protein inhibitors (DPCs). The lead compound, ARV- 1501, imparts its antimicrobial activity in two distinct ways; i) disrupting the bacterial lipid membrane and ii) specifically inhibiting the bacterial chaperone protein DnaK, a highly conserved prokaryotic heat-shock protein critical for bacterial survival in stress conditions. In preliminary studies, ARV-1502 has demonstrated broad-spectrum antimicrobial activity against a range of Gram-negative and Gram-positive bacterial pathogens. ARV-1502 has also demonstrated the ability to reverse bacterial resistance to legacy antibiotics. In the proposed Phase I program, Arrevus will conduct a series of studies to characterize the antibiotic activities of ARV-1502 both in vitro and in vivo in order to assess the potential of ARV-1502, alone and in combination with an antibiotic, to treat HAP and VAP. In Aim 1, we will use in vitro studies to define the spectrum of activity of ARV-1502 alone (Aim 1A) and in combination with clinically-utilized antibiotics (Aim 1B) against antibiotic-sensitive and antibiotic-resistant strains of P. aeruginosa. In Aim 2, we will assess ARV-1502 alone and as an adjuvant therapy with the meropenem in a mouse model of pneumonia. In Aim 2A, ARV-1502 will be administered as a monotherapy to characterize efficacy and dosing for co-treatment in Aim 2B. The collective data from this Phase I effort will define ARV-1502?s ability, alone or with an antibiotic, to treat pneumonia that is typically resistant to legacy antibiotics. These proof-of-concept data are critical to support further development of ARV-1502 in a Phase II program that would be geared toward performing extensive in vivo efficacy and safety studies to assess ARV-1502 as a therapeutic option for treating MDR-associated HAP and VAP.